A role for a RhoA/ROCK/LIM-kinase pathway in the regulation of cytotoxic lymphocytes

被引:43
作者
Lou, ZK
Billadeau, DD
Savoy, DN
Schoon, RA
Leibson, PJ
机构
[1] Mayo Clin & Mayo Fdn, Dept Immunol, Mayo Grad Sch, Rochester, MN 55905 USA
[2] Mayo Clin & Mayo Fdn, Dept Immunol, Mayo Med Sch, Rochester, MN 55905 USA
[3] Mayo Clin & Mayo Fdn, Dept Pharmacol, Mayo Grad Sch, Rochester, MN 55905 USA
[4] Mayo Clin & Mayo Fdn, Dept Pharmacol, Mayo Med Sch, Rochester, MN 55905 USA
关键词
D O I
10.4049/jimmunol.167.10.5749
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Polarization of lipid rafts and granules to the site of target contact is required for the development of cell-mediated killing by cytotoxic lymphocytes. We have previously shown that these events require the activation of proximal protein tyrosine kinases. However, the downstream intracellular signaling molecules involved in the development of cell-mediated cytotoxicity remain poorly defined. We report here that a RhoA/ROCK/LIM-kinase axis couples the receptor-initiated protein tyrosine kinase activation to the reorganization of the actin cytoskeleton required for the polarization of lipid rafts and the subsequent generation of cell-mediated cytotoxicity. Pharmacologic and genetic interruption of any element of this RhoA/ROCK/LIM-kinase pathway inhibits both the accumulation of F-actin and lipid raft polarization to the site of target contact and the subsequent delivery of the lethal hit. These data define a specialized role for a RhoA --> ROCK --> LIM-kinase pathway in cytotoxic lymphocyte activation.
引用
收藏
页码:5749 / 5757
页数:9
相关论文
共 48 条
[1]   The function of small GTPases in signaling by immune recognition and other leukocyte receptors [J].
Altman, A ;
Deckert, M .
ADVANCES IN IMMUNOLOGY, VOL. 72, 1999, 72 :1-101
[2]  
Angkachatchai V, 1999, J IMMUNOL, V163, P3819
[3]   Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase [J].
Arber, S ;
Barbayannis, FA ;
Hanser, H ;
Schneider, C ;
Stanyon, CA ;
Bernard, O ;
Caroni, P .
NATURE, 1998, 393 (6687) :805-809
[4]   The Rho family guanine nucleotide exchange factor Vav-2 regulates the development of cell-mediated cytotoxicity [J].
Billadeau, DD ;
Mackie, SM ;
Schoon, RA ;
Leibson, PJ .
JOURNAL OF EXPERIMENTAL MEDICINE, 2000, 192 (03) :381-391
[5]   The Vav-Rac1 pathway in cytotoxic lymphocytes regulates the generation of cell-mediated killing [J].
Billadeau, DD ;
Brumbaugh, KM ;
Dick, CJ ;
Schoon, RA ;
Bustelo, XR ;
Leibson, PJ .
JOURNAL OF EXPERIMENTAL MEDICINE, 1998, 188 (03) :549-559
[6]   Functional role for Syk tyrosine kinase in natural killer cell-mediated natural cytotoxicity [J].
Brumbaugh, KM ;
Binstadt, BA ;
Billadeau, DD ;
Schoon, RA ;
Dick, CJ ;
Ten, RM ;
Leibson, PJ .
JOURNAL OF EXPERIMENTAL MEDICINE, 1997, 186 (12) :1965-1974
[7]   Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics [J].
Edwards, DC ;
Sanders, LC ;
Bokoch, GM ;
Gill, GN .
NATURE CELL BIOLOGY, 1999, 1 (05) :253-259
[8]   TYROSINE PHOSPHORYLATION PROVIDES AN EARLY AND REQUISITE SIGNAL FOR THE ACTIVATION OF NATURAL-KILLER-CELL CYTOTOXIC FUNCTION [J].
EINSPAHR, KJ ;
ABRAHAM, RT ;
BINSTADT, BA ;
UEHARA, Y ;
LEIBSON, PJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (14) :6279-6283
[9]   FC-EPSILON-RI-MEDIATED RECRUITMENT OF P53/56(LYN) TO DETERGENT-RESISTANT MEMBRANE DOMAINS ACCOMPANIES CELLULAR SIGNALING [J].
FIELD, KA ;
HOLOWKA, D ;
BAIRD, B .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (20) :9201-9205
[10]   Vav is a regulator of cytoskeletal reorganization mediated by the T-cell receptor [J].
Fischer, KD ;
Kong, YY ;
Nishina, H ;
Tedford, K ;
Marengère, LEM ;
Kozieradzki, I ;
Sasaki, T ;
Starr, M ;
Chan, G ;
Gardener, S ;
Nghiem, MP ;
Bouchard, D ;
Barbacid, M ;
Bernstein, A ;
Penninger, JM .
CURRENT BIOLOGY, 1998, 8 (10) :554-562